Electrical pacemaker activity serves a critical function in gastric motility. Recent studies have determined that interstitial cells of Cajal (ICC), located in the myenteric region of the tunica muscularis of the corpus and antrum, are the primary pacemaker cells in mammalian gastric muscles. Pacemaker events, originating near the greater curvature of the corpus, spread around and down the stomach to the pyloric sphincter. This activity, known as electrical stow waves, times the occurrence of gastric peristaltic contractions. Proper spread of slow waves depends upon a proximal-to-distal gradient in the intrinsic frequency of pacemaker activity. Loss of pacemaker activity, emergence of ectopic pacemakers, or defects in slow wave propagation can lead to functional motility disorders of the stomach. This project will seek to understand the pacemaker mechanisms in gastric ICC. Studies will be performed on isolated ICC from the corpus and antrum to determine the conductance(s) responsible for pacemaker currents and the intracellular events leading to activation of pacemaker currents. We have found that the gastric pacemaker frequency gradient is encoded in ICC from the corpus and antrum, and further experiments will carefully attempt to dissect the differences in pacemaker activity of the ICC from these regions to understand the basis for the pacemaker frequency gradient. We will also determine whether the mechanisms responsible for generation of pacemaker current are required for regeneration of slow waves, and experiments will be performed to understand how electrical pacing from an external current source can affect generation and propagation of slow waves. Experiments to determine the factors involved in regulation of pacemaker frequency in ICC and to determine the mechanisms by which various biogenic chemicals affect the timing of pacemaker events will be performed. This information may provide new insights into the causes (and perhaps cures) for gastric arrhythmias. Basic information about generation, propagation and regulation of pacemaker frequency will be used in studies of intact muscles to explore the nature of the gastric frequency gradient and how changes in pacemaker frequency affect the spread of slow waves (i.e. functional coupling) between the corpus and antrum. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling. [unreadable] [unreadable] [unreadable]